Adenosine is a naturally occurring nucleoside, which exerts its biological effects by interacting with a family of adenosine receptors known as A1, A2a, A2b, and A3, all of which modulate important physiological processes. For example, A2A adenosine receptors modulate coronary vasodilation, A2B receptors have been implicated in mast cell activation, asthma, vasodilation, regulation of cell growth, intestinal function, and modulation of neurosecretion (See Adenosine A2B Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistov et al., Trends Pharmacol Sci 19:148–153), and A3 adenosine receptors modulate cell proliferation processes.
A1 adenosine receptor agonists modulates the cardiostimulatory effects of catecholamine (mediated via the inhibition of adenylate cyclase), and slow the heart rate (HR) and prolong impulse propagation through the AV node, which is due in great part to activation of IKAdo. (B. Lerman and L. Belardinelli Circulation, Vol. 83 (1991), P 1499–1509 and J. C. Shryock and L. Belardinelli The Am. J. Cardiology, Vol. 79 (1997) P 2–10). Stimulation of the A1 adenosine receptor shortens the duration and decreases the amplitude of the action potential of AV nodal cells, and hence prolongs the refractory period of the AV nodal cell. Thus, stimulation of A1 receptors provides a method of treating supraventricular tachycardias, including termination of nodal re-entrant tachycardias, and control of ventricular rate during atrial fibrillation and flutter.
Elevated serum levels of non-esterified free fatty acid (NEFA) are detrimental to both the mechanical and electrical function of the heart, and A1 adenosine receptor agonists are potent and efficacious inhibitors of lipolysis. Importantly, because A1 adenosine receptor agonists are more potent in adipose tissue that in heart tissues, they decrease lipolysis at concentrations that do not affect heart rate. Thus, A1 adenosine receptor agonists are useful for treating metabolic disorders such as non-insulin-dependent diabetes mellitus and obesity via their anti-lipolytic activity. The antilipolytic effect of adenosine A1 receptor agonists is also useful in the management of congestive heart failure. Furthermore, A1 adenosine receptor agonists are protective against cardioischemia. A1 adenosine receptor agonists are also useful as chemotherapeutics in the treatment of CNS disorders including epilepsy (anticonvulsant activity) and ischemia.
Accordingly, it is an object of this invention to provide compounds that are potent full A1 adenosine receptor agonists or partial A1 adenosine receptor agonists. Preferred compounds of the invention are selective for the A1 adenosine receptor, which minimizes undesired side effects related to stimulation or antagonism of the other adenosine receptors.